Valtrex (Valacyclovir Hydrochloride) - Description and Clinical Pharmacology

DESCRIPTION

VALTREX (valacyclovir hydrochloride) is the hydrochloride salt of the L -valyl ester of the antiviral drug acyclovir.

VALTREX Caplets are for oral administration. Each caplet contains valacyclovir hydrochloride equivalent to 500 mg or 1 gram valacyclovir and the inactive ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide. The blue, film-coated caplets are printed with edible white ink.

The chemical name of valacyclovir hydrochloride is L -valine, 2-[(2-amino-1,6-dihydro-6-oxo-9 H -purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula:

Valacyclovir hydrochloride is a white to off-white powder with the molecular formula C₁₃H₂₀N₆O₄•HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is 174 mg/mL. The pk_as for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.

CLINICAL PHARMACOLOGY

Mechanism of Action

Valacyclovir is an antiviral drug [see Clinical Pharmacology].

Pharmacokinetics

The pharmacokinetics of valacyclovir and acyclovir after oral administration of VALTREX have been investigated in 14 volunteer studies involving 283 adults and in 3 studies involving 112 pediatric subjects from 1 month to <12 years of age.

Pharmacokinetics in Adults: Absorption and Bioavailability: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L- valine by first-pass intestinal and/or hepatic metabolism.

The absolute bioavailability of acyclovir after administration of VALTREX is 54.5% ± 9.1% as determined following a 1 gram oral dose of VALTREX and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of VALTREX is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).

Acyclovir pharmacokinetic parameter estimates following administration of VALTREX to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (C_max) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of VALTREX from doses between 250 mg to 1 gram.

There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.

Table 3. Mean (±SD) Plasma Acyclovir Pharmacokinetic Parameters Following Administration of VALTREX to Healthy Adult Volunteers

Dose	Single-Dose Administration (N = 8)		Multiple-Dose Administration* (N = 24, 8 per treatment arm)
	Cmax (±SD) (mcg/mL)	AUC (±SD) (hrâ—�mcg/mL)	Cmax (±SD) (mcg/mL)	AUC (±SD) (hrâ—�mcg/mL)
100 mg	0.83 (±0.14)	2.28 (±0.40)	ND	ND
250 mg	2.15 (±0.50)	5.76 (±0.60)	2.11 (±0.33)	5.66 (±1.09)
500 mg	3.28 (±0.83)	11.59 (±1.79)	3.69 (±0.87)	9.88 (±2.01)
750 mg	4.17 (±1.14)	14.11 (±3.54)	ND	ND
1,000 mg	5.65 (±2.37)	19.52 (±6.04)	4.96 (±0.64)	15.70 (±2.27)
* Administered 4 times daily for 11 days.
ND = not done.

Distribution: The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.

Metabolism: Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of VALTREX, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers who received concomitant cimetidine and probenecid, respectively.

Elimination: The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1 gram dose of VALTREX to 12 healthy volunteers was approximately 255 ± 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.

The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all studies of VALTREX in volunteers with normal renal function.

Specific Populations: Renal Impairment: Reduction in dosage is recommended in patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.5),].

Following administration of VALTREX to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3 mL/min/1.73 m² compared with 679.16 ± 162.76 mL/min/1.73 m² in healthy volunteers.

Hepatic Impairment: Administration of VALTREX to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis.

HIV Disease: In 9 patients with HIV disease and CD4+ cell counts <150 cells/mm³ who received VALTREX at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy volunteers.

Geriatrics: After single-dose administration of 1 gram of VALTREX in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy younger adult volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of VALTREX in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient [see Dosage and Administration (2.4), Use in Specific Populations (8.5),].

Pediatrics: Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric patients (1 month to <12 years of age) following administration of the first dose of an extemporaneous oral suspension of valacyclovir [see Adverse Reactions (6.2), Use in Specific Populations]. Acyclovir pharmacokinetic parameter estimates following a 20 mg/kg dose are provided in Table 4.

Table 4. Mean (±SD) Plasma Acyclovir Pharmacokinetic Parameter Estimates Following First-Dose Administration of 20 mg/kg Valacyclovir Oral Suspension to Pediatric Patients vs. 1 Gram Single Dose of VALTREX to Adults

* Historical estimates using pediatric pharmacokinetic sampling schedule.
Parameter	Pediatric Patients (20 mg/kg Oral Suspension)			Adults 1 gram Solid Dose of VALTREX* (N = 15)
	1 - <2 yr (N = 6)	2 - <6 yr (N = 12)	6 - <12 yr (N = 8)
AUC (mcg•hr/mL)	14.4 (±6.26)	10.1 (±3.35)	13.1 (±3.43)	17.2 (±3.10)
Cmax (mcg/mL)	4.03 (±1.37)	3.75 (±1.14)	4.71 (±1.20)	4.72 (±1.37)

Drug Interactions: When VALTREX is coadministered with antacids, cimetidine and/or probenicid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when VALTREX is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.

Antacids: The pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) were unchanged by coadministration of a single dose of antacids (Al³⁺ or Mg⁺⁺).

Cimetidine: Acyclovir C_max and AUC following a single dose of VALTREX (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).

Cimetidine Plus Probenecid: Acyclovir C_max and AUC following a single dose of VALTREX (1 gram) increased by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir.

Digoxin: The pharmacokinetics of digoxin were not affected by coadministration of VALTREX 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).

Probenecid: Acyclovir C_max and AUC following a single dose of VALTREX (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).

Thiazide Diuretics: The pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.

Microbiology

Mechanism of Action: Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo.

The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.

Antiviral Activities: The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC₅₀), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC₅₀ values against herpes simplex virus isolates range from 0.09 to 60 Î¼M (0.02 to 13.5 mcg/mL) for HSV-1 and from 0.04 to 44 Î¼M (0.01 to 9.9 mcg/mL) for HSV-2. The EC₅₀ values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 Î¼M (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC₅₀ of 6 Î¼M (1.35 mcg/mL).

Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered.

Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram VALTREX given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir [see Clinical Pharmacology].

Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors.

Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study.

In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic.

Valacyclovir was mutagenic in a mouse micronucleus assay.

Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels.

CLINICAL STUDIES

Cold Sores (Herpes Labialis)

Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (≥12 years old) with a history of recurrent cold sores. Patients self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms. Patients were randomized to VALTREX 2 grams twice daily on Day 1 followed by placebo on Day 2, VALTREX 2 grams twice daily on Day 1 followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2.

The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared with placebo. The 2 day regimen did not offer additional benefit over the 1-day regimen.

No significant difference was observed between subjects receiving VALTREX or placebo in the prevention of progression of cold sore lesions beyond the papular stage.

Genital Herpes Infections

Initial Episode: Six hundred and forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of VALTREX 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). For both treatment groups: the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, the median time to cessation of viral shedding was 3 days.

Recurrent Episodes: Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.

In 1 study, patients were randomized to receive 5 days of treatment with either VALTREX 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving VALTREX 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.

In a third study, patients were randomized to receive VALTREX 500 mg twice daily for 5 days (n = 398) or VALTREX 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.

Suppressive Therapy: Two clinical studies were conducted, one in immunocompetent adults and one in HIV-infected adults.

A double-blind, 12-month, placebo- and active-controlled study enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall study population are shown in Table 5.

Table 5. Recurrence Rates in Immunocompetent Adults at 6 and 12 Months

* Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.
Outcome	6 Months			12 Months
	VALTREX 1 gram once daily (n = 269)	Oral acyclovir 400 mg twice daily (n = 267)	Placebo (n = 134)	VALTREX 1 gram once daily (n = 269)	Oral acyclovir 400 mg twice daily (n = 267)	Placebo (n = 134)
Recurrence free	55%	54%	7%	34%	34%	4%
Recurrences	35%	36%	83%	46%	46%	85%
Unknown*	10%	10%	10%	19%	19%	10%

Subjects with 9 or fewer recurrences per year showed comparable results with VALTREX 500 mg once daily.

In a second study, 293 HIV-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either VALTREX 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months. The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median prestudy HIV-1 RNA was 2.6 log₁₀ copies/mL. Among patients who received VALTREX, the prestudy median CD4+ cell count was 336 cells/mm³; 11% had <100 cells/mm³, 16% had 100 to 199 cells/mm³, 42% had 200 to 499 cells/mm³, and 31% had ≥500 cells/mm³. Outcomes for the overall study population are shown in Table 6.

Table 6. Recurrence Rates in HIV-Infected Adults at 6 Months

* Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.
Outcome	VALTREX 500 mg twice daily (n = 194)	Placebo (n = 99)
Recurrence free	65%	26%
Recurrences	17%	57%
Unknown*	18%	17%

Reduction of Transmission of Genital Herpes: A double-blind, placebo-controlled study to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The source partner had a history of 9 or fewer genital herpes episodes per year. Both partners were counseled on safer sex practices and were advised to use condoms throughout the study period. Source partners were randomized to treatment with either VALTREX 500 mg once daily or placebo once daily for 8 months. The primary efficacy endpoint was symptomatic acquisition of HSV-2 in susceptible partners. Overall HSV-2 acquisition was defined as symptomatic HSV-2 acquisition and/or HSV-2 seroconversion in susceptible partners. The efficacy results are summarized in Table 7.

Table 7. Percentage of Susceptible Partners Who Acquired HSV-2 Defined by the Primary and Selected Secondary Endpoints

* Results show reductions in risk of 75% (symptomatic HSV-2 acquisition), 50% (HSV-2 seroconversion), and 48% (overall HSV-2 acquisition) with VALTREX versus placebo. Individual results may vary based on consistency of safer sex practices.
Endpoint	VALTREX* (n = 743)	Placebo (n = 741)
Symptomatic HSV-2 acquisition	4 (0.5%)	16 (2.2%)
HSV-2 seroconversion	12 (1.6%)	24 (3.2%)
Overall HSV-2 acquisition	14 (1.9%)	27 (3.6%)

Herpes Zoster

Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. VALTREX was compared with placebo in patients less than 50 years of age, and with oral acyclovir in patients greater than 50 years of age. All patients were treated within 72 hours of appearance of zoster rash. In patients less than 50 years of age, the median time to cessation of new lesion formation was 2 days for those treated with VALTREX compared with 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either VALTREX or oral acyclovir. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of VALTREX and placebo. In patients greater than 50 years of age, among the 83% who reported pain after healing (post-herpetic neuralgia), the median duration of pain after healing [95% confidence interval] in days was: 40 [31, 51], 43 [36, 55], and 59 [41, 77] for 7-day VALTREX, 14-day VALTREX, and 7-day oral acyclovir, respectively.

Chickenpox

The use of VALTREX for treatment of chickenpox in pediatric patients 2 to <18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by safety and extrapolated efficacy data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients.

The single-dose pharmacokinetic and multiple-dose safety study enrolled 27 pediatric patients 1 to <12 years of age with clinically suspected VZV infection. Each subject was dosed with valacyclovir oral suspension, 20 mg/kg 3 times daily for 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of herpes zoster. The mean projected daily acyclovir exposures in pediatric patients across all age-groups (1 to <12 years of age) were lower (C_max: ↓13%, AUC: ↓30%) than the mean daily historical exposures in adults receiving valacyclovir 1 gram 3 times daily, but were higher (daily AUC: ↑50%) than the mean daily historical exposures in adults receiving acyclovir 800 mg 5 times daily. The projected daily exposures in pediatric patients were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric patients receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox. Based on the pharmacokinetic and safety data from this study and the safety and extrapolated efficacy data from the acyclovir studies, oral valacyclovir 20 mg/kg 3 times a day for 5 days (not to exceed 1 gram 3 times daily) is recommended for the treatment of chickenpox in pediatric patients 2 to <18 years of age. Because the efficacy and safety of acyclovir for the treatment of chickenpox in children <2 years of age have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children <2 years of age with chickenpox. Valacyclovir is also not recommended for the treatment of herpes zoster in children because safety data up to 7 days’ duration are not available [see Use in Specific Populations].